CHEMICAL SYNTHESIS AND BIOLOGICAL-ACTIVITY OF A NOVEL FLUORESCENT ETOPOSIDE DERIVATIVE

The antineoplastic activity of etoposide resides in its ability to poi son the nuclear enzyme DNA topoisomerase II (topo II). The factors tha t control the cellular entry and subcellular distribution of etoposide remain poorly understood. Therefore, we have synthesized a novel fluo rescence-labeled etoposide (Bodipyetoposide) by coupling -3a,4a-diaza- s-indacene-3-propionylethylenediamine (Bodipy) to 4'-benzyloxycarbonyl -4'-demethylepipodophyllotoxin beta-D-glucopyranoside, a precursor of etoposide. Bodipy-etoposide retained the ability to stabilize topo II- DNA covalent complexes in isolated nuclei, although it was significant ly less potent and efficacious than etoposide; The growth inhibitory a ctivity of Bodipy-etoposide was also approximately 200-fold less than that of etoposide in human leukemia K562 and DU-145 prostatic carcinom a cells. Nonetheless, etoposide-resistant K/VP.5 and K/VP.5-1 leukemia cells were cross-resistant to Bodipy-etoposide compared with parental K562 cells. Analysis by flow cytometry revealed a concentration-depen dent Bodipy-etoposide cell association with no significant difference in drug association in the etoposide-resistant cell lines relative to the parental K562 cells. Using confocal laser scanning microscopy, we found significant cytoplasmic perinuclear localization of Bodipy-etopo side. Thus, Bodipy-etoposide displays promise as a tool to probe the f actors controlling entry and subcellular distribution of etoposide-lik e compounds in live cells. (C) 1997 Elsevier Science Inc.